NH-1,2,3-triazoles as versatile building blocks in denitrogenative transformations

The utilization of NH-1,2,3-triazoles as easily accessible building blocks in denitrogenative ring cleavage transformations with electrophiles to provide multifunctionalized nitrogen heterocycles and N-alkenyl compounds is reviewed. Leveraging the ready availability of NH-1,2,3-triazoles, these processes provide a convenient route to a range of pharmaceutically relevant heterocyclic cores and N-alkenyl compounds. The synthetic usefulness of in situ acylated NH-1,2,3-triazoles as viable alternatives to widely explored N-sulfonyl-1,2,3-triazoles in ring cleavage processes is highlighted.

1,2,3-Triazoles are nitrogen heterocycles with versatile reactivity 1 and great medicinal importance. 2 Since the discovery of azide-alkyne click chemistry in 2002, 3 triazole derivatives have gained enormous attention in organic, medicinal, biomolecular, and material sciences.Among them, 1,2,3-triazoles bearing an electron-withdrawing group at position N1 are of special importance because of their propensity to undergo N1-N2 bond cleavage in denitrogenative triazole ring opening transformations (Scheme 1a). 1 N-sulfonyl-1,2,3-triazoles 4 and N-uoroalkyl-1,2,3-triazoles 5 are the most explored building blocks, which undergo ring cleavage under metal catalysis or by the action of Lewis or Brønsted acids.Very recently, a new strategy based on the use of NH-1,2,3-triazoles involving the installation of an electron-withdrawing group with in situ ring cleavage was described and used with success (Scheme 1b).The present review features the use of free NH-1,2,3-triazoles 1 in denitrogenative transformations, proceeding via N-acyl-1,2,3triazoles or their analogues as key intermediates.
N-unsubstituted NH-1,2,3-triazoles 1, considered in the present review, are the simplest and most readily available triazoles. 6They can be prepared by azide-alkyne cycloaddition 6 or alternative methods such as cycloaddition/elimination with activated ketones 7 or nitroalkenes. 7In the last ve years, there has been a notable surge of innovative methods for the synthesis of NH-1,2,3-triazoles and several one-pot protocols from inexpensive and commercially available reagents have been developed. 6To underline the most efficient and practical routes, NH-1,2,3-triazoles were synthesized from TMSN 3 and alkynes via CuI-catalysed cycloaddition (Scheme 2a), 8 or sodium azide, aldehydes and nitroalkanes via a tandem Henry reaction/ [3 + 2] cycloaddition (Scheme 2b), 9a-c including recently developed green chemistry approaches.9d-h In 2022, NH-1,2,3-triazoles became available from NaN 3 /H 2 SO 4 and alkynes, which is so far the simplest and the most straightforward route, although the generation of HN 3 raises safety concerns (Scheme 2c). 10 Finally, the approach utilizing azidyl radical-alkyne cycloaddition with the use of the NaN 3 /PhI(OAc) 2 system in mild conditions is highly efficient for complex disubstituted triazoles such as 4,5-diaryltriazoles (Scheme 2d), 11a and it was also possible to efficiently synthesize these compounds without an oxidant, albeit only under harsh conditions (MW heating at 200 °C).11b More examples of novel synthetic methods to access NH-1,2,3-triazoles appeared in recent reviews. 6ue to better atom economy, the utilization of readily available NH-triazoles is advantageous compared to the use of N-sulfonyl-or N-uoroalkyl-triazoles.Additionally, access to NH-1,2,3-triazoles was possible using "alkyne-free" methods.Both, primary nitro compounds and aromatic aldehydes are easily accessible industrial scale products. 12ne of the rst denitrogenative transformations of 1,2,3-NHtriazoles 1 was reported in 2014.In this process, in situ sulfonylation with triic anhydride and 2,6-di(tert-butyl)-4methylpyridine (DTBMP) as a base was used to generate reactive N-triyl triazoles 2. 13 Their ring cleavage by a chiral Rh(II) catalyst in the presence of an excess of alkene 3 afforded 2,3dihydropyrroles 4 with low to good enantiocontrol (Scheme 3).
However, besides triation, there are no other examples of in situ sulfonylation of NH-1,2,3-triazoles followed by denitrogenative transformations.Therefore, this reaction is limited to the extremely electron-accepting triyl group and analogous ring cleavage did not proceed with other N-sulfonyl triazoles.
In contrast to sulfonylation, acylation of NH-1,2,3-triazoles is more versatile and has developed into a highly active area of research in recent years. 14Tandem acylation followed by ring cleavage without isolation of N-acyltriazoles was performed using acyl halides or acid anhydrides.The mechanism of this transformation, recently conrmed by us, 14 involved the formation of N1 (5) and N2-acylated (6) triazoles in equilibrium, followed by acid-mediated cleavage of the former.Denitrogenation and formation of a vinyl cation in an irreversible step was the driving force of N2-N1-acyltriazole interconversion, which ensured the complete transformation of triazoles into ring cleavage products 7-9 (Scheme 4).
Cleavage of NH-1,2,3-triazoles 1 with an excess of acyl halides 10 (X = Cl, Br) under elevated temperature led to the formation of b-enamido halides 9 in moderate to good yields (Scheme 5). 15-Enamido halides are difficult to access by other synthetic routes and are present in natural products, which underlines the synthetic value of the method.This transformation in the presence of sodium sulfonates was employed in the synthesis of enamido triates or sulfonates 11.Mainly compounds with the phenacyl group at the nitrogen were accessed by the mentioned route (Scheme 6).15 An alternative method, applicable to the synthesis of b-uoroacylenamido triates is based on the formation of N2acyltriazoles 6 via the in situ acylation of NH-1,2,3-triazoles with uorinated acid anhydrides followed by their treatment with triic acid, which proceeds through N2-N1 acyltriazole interconversion and ring cleavage (Scheme 7).14 The products are useful building blocks, that can get involved in Pd-catalysed cross-coupling substitution reactions of the triate group to access multifunctionalized enamide derivativesattractive drug candidates and synthetic intermediates.16 None of the methods mentioned was applicable with the less reactive alkyl-substituted acylating agents (Ac 2 O, AcCl), because the resulting acyltriazoles were resistant to ring cleavage even at elevated temperatures.14 The cleavage of NH-1,2,3-triazoles with an excess of uoroalkylated acid anhydrides led to highly pharmaceutically relevant 2-uoroalkyl oxazoles 7 (in the cases of 4,5-disubstituted triazoles) or 2-acylaminoketones (for 4-substituted triazoles, R = H) (Scheme 8).17 In the rst case intramolecular cyclization took place, whereas in the second, unstable b-acyloxyenamide 8 ′ formed, which underwent ester hydrolysis to 2acylaminoketone 8 upon treatment with an aqueous base.The difference in chemoselectivity was attributed to the increased vinyl cation stability of disubstituted which made them more prone to intramolecular cyclization.
4,5-disubstituted NH-1,2,3-triazole reacted with trichloroacetic anhydride to give 2-unsubstituted oxazole 13, due to the low stability of the trichloromethyl-substituted product 12 during silica gel column chromatography.The whole transformation is a rare and unique case of a reaction involving trichloroacetic anhydride as a one-carbon building block (Scheme 9). 17e limitation of oxazole synthesis to only disubstituted triazoles was overcome by the cyclization of in situ formed bacyloxyenamide 8 ′ to oxazoles 7 using Et 3 N and proceeded quickly and nearly quantitatively under ambient conditions. 18his one-pot triazole cleavage procedure provided an efficient access to 2-uoroalkylated oxazoles from monosubstituted triazoles in good to excellent yields (Scheme 10).
The easy access to uorinated 2-acylaminoketones 8 was utilized in a number of one-pot syntheses of uoroalkylated heterocycles directly from NH-1,2,3-triazoles 1. First, 2-uoroalkyl imidazoles 14 were prepared by cleavage with triuoroacetic or peruoropropanoic anhydrides, followed by the treatment of the ketamide intermediate with an aqueous solution of the primary amine (or ammonium acetate for R = H) under microwave conditions.The acid formed aer hydrolysis of the enamide to yield 2-acylaminoketone promoted the Robinson-Gabriel cyclization of the latter.This procedure afforded imidazoles 14 in moderate to good yields in a one-pot manner starting from triazoles (Scheme 11). 17 Alternatively, condensation of the formed acyloxyenamide 8 ′ with hydrazine hydrate aer switching the solvent to acetic acid provided uoroalkylated 1,2,4-triazines 15 (Scheme 12). 17he formation of the vinyl cation intermediate in N-acyltriazole cleavage was conrmed by changing the solvent from a chlorinated one to acetonitrile or propionitrile. 18In one special case (Scheme 13, R = p-Tol) adducts 16 of the Ritter reaction were formed and hydrolysed to bis(enamides) 17.However, this reaction was not general and in the cases of electron-richer triazoles, cyclization of the vinyl cation to oxazoles 7 took place (Scheme 13, R = H, EDG).This route is an alternative to one mentioned above (Scheme 10), and is applicable to electron-rich substrates.The straightforward formation of oxazoles 7 rather than enamides 8 ′ in polar MeCN was explained by the decreased stability of the vinyl cation-tri-uoroacetate anion contact ion pair, which prevented recombination and favoured cyclization. 18everal efficient NH-1,2,3-triazole ring cleavage protocols were also developed for NH-benzotriazole 18, which can be easily and regioselectively acylated on N1.The treatment of the formed N-acylbenzotriazole 20 with AlCl 3 as a Lewis acid promotor facilitated ring cleavage leading to benzoxazoles under relatively harsh conditions (Scheme 14). 19are examples of ortho-iodoacetanilide 22 formation in moderate yields from NH-and related N-acylbenzotriazole were reported in which the All 3 /Ac 2 O system or aluminium and iodine in acetonitrile were used. 20These are the only cases of Nacetylbenzotriazole 23 ring cleavage known.Importantly, the reaction of N-acetylbenzotriazole 23 with AlCl 3 was not efficient and led only to deacylation, and not to the desired ring cleavage product (Scheme 15). 19leavage of electron-rich 4-aryl-NH-1,2,3-triazoles 1 was successfully achieved with thiophosgene leading to the formation of vinyl isothiocyanates 24 by HCl elimination from the vinyl chloride intermediate (Scheme 16). 21The vinyl isothiocyanate moiety is present in natural products with antifungal and antibacterial activity and is difficult to access by traditional methods.Switching from electron-rich aromatic NHtriazoles to unsubstituted NH-1,2,3-triazole afforded product 25 of HCl addition across the double bond in moderate yield.
A similar transformation with triazoles 1 bearing an electron-rich aryl or alkenyl substituent in position 4 proceeded with triphosgene. 21The in situ formed carbamoyl chlorides 26 were treated with nucleophiles to gain access to multifunctional compounds 27, such as N-alkenyl carbamates, ureas and thiocarbamates (Scheme 17).
The denitrogenative transformation of NH-1,2,3-triazoles was studied also on more complex substrates such as 4-(1hydroxycyclobutyl)-1,2,3-triazoles 28.Their cleavage with acyl chlorides 10 catalysed by triic acid provided efficient access to cyclic enaminones 29 (Scheme 18). 22The reaction proceeded via the cleavage of N-acyltriazole and semipinacol rearrangement cascade.The procedure was found to be easily scalable to give multifunctional substrates in good yields.

Conclusions
In conclusion, NH-1,2,3-triazoles are commercially available or easily synthesized starting materials that exhibit a remarkable versatility in transformations to diverse nitrogen-containing heterocycles and functionalized N-alkenyl compounds via denitrogenative cleavage.In situ prepared N-acylated 1,2,3-triazoles are key intermediates in these transformations.Acidmediated triazole ring opening of N-acylated 1,2,3-triazoles, followed by nitrogen elimination affords vinyl cation intermediates, which undergo a variety of reactions such as cyclization or heteroatom capture.Further development of denitrogenation of NH-1,2,3-triazoles accompanied by C-C bond forming reactions, C-H insertion or rearrangement of the vinyl cation can be expected, providing access to a structural diversity of products with potential applications in drug development.Moreover, due to easy availability of NH-1,2,3-triazoles they are excellent starting materials for the development of new industrial synthetic processes.